There are compelling data linking human herpesvirus 6 (HHV-6) reactivation and serious central nervous system (CNS) dysfunction including encephalitis and seizures following hematopoietic stem cell transplant (HSCT). Despite appropriate therapy, HHV-6 CNS dysfunction is associated with high mortality and morbidity. While antiviral therapy may abrogate viremia and detectable levels of virus in CSF, the toxicity of the drugs of choice, ganciclovir and foscamet, are high and the clinical effects of such therapy uncertain. Preemptive or prophylactic approaches may result in better clinical outcomes, but before such approaches can be tested, the spectrum, incidence, and outcomes of HHV-6 CNS dysfunction following HSCT as well as its risk factors need to be defined. Our preliminary data from a prospective pilot study of delirium after HSCT suggests an association between HHV-6 and CNS dysfunction. Also, a summary of patients with HHV-6 encephalitis from our center suggests that there may be lasting neurological sequelae in the majority of survivors. Thus, we hypothesize that HHV-6 reactivation after HSCT is associated with a larger spectrum of CNS dysfunction than currently recognized and that this leads to persistent, severe cognitive abnormalities. Aim 1. To evaluate the association between HHV-6 reactivation and CNS dysfunction and to define the spectrum and incidence of CNS dysfunction preceded by HHV-6 reactivation. Aim 2. To define the long-term outcomes of HHV-6 associated CNS dysfunction following HSCT. We propose a large prospective study of HSCT recipients. Patients' plasma will be screened twice weekly for HHV-6 using a real-time quantitative fluorescent-probe polymerase chain reaction (PCR) assay. All CSF specimens obtained for routine or urgent purposes will also be tested for HHV-6. Patients will be screened three times weekly for CNS dysfunction using validated neuropsychiatric instruments that have been used successfully in HSCT recipients. Neuropsychological testing will be performed at three time points during the study to define short- and long-term cognitive sequelae associated with HHV-6 CNS dysfunction. Data from this project will not only inform current diagnosis of and prognosis for HHV-6 CNS dysfunction, but will also be used to design an intervention trial.